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A pharmacokinetic-dynamic explanation of the rapid onsetoffset of rapacuronium

Proost, J. H.1; Wright, P. M. C.2

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European Journal of Anaesthesiology: November 2001 - Volume 18 - Issue - p 83-89
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Abstract

Introduction

The time-course of action of any drug is governed by its pharmacokinetic (PK) and pharmacodynamic (PD) properties. Therefore, to explain the rapid onset and offset of rapacuronium, we need to understand the processes and mechanisms governing its PK and PD. PK–PD modelling and analyses are useful tools to explore the PK–PD relationships, and to gain insight into the processes responsible for the time-course of action [1,2].

PK–PD models consist of three elements: (a) a PK model, describing the time-course of the plasma concentration following a bolus dose or infusion of the drug, (b) a PK–PD link model, relating the concentration at the receptor site or effect compartment to the plasma concentration and (c) a PD model relating the drug effect to the compartment concentration. In the commonly applied PK–PD model proposed by Sheiner and colleagues [1] it is assumed that the concentration of the neuromuscular blocking agent in the effect compartment (also denoted the receptor site or the biophase; for neuromuscular blocking agents the terms neuromuscular junction or synaptic cleft refer to the same site) equals the plasma concentration during steady state. The PD model is characterized by the NMBA concentration at 50% block (EC50, also denoted C p50ss or C50), and the steepness of the concentration–effect relationship, or the Hill factor (γ). The PK–PD link model is characterized by the rate constant of transport of the NMBA between plasma and effect compartment (ke0).

The objective of this paper is to review the possible explanations for the rapid onset and offset of neuromuscular block after an intubation dose of rapacuronium. In this review, the term ‘effective potency’ refers to the bolus dose needed to reach a specified maximal neuromuscular block (e.g. ED95) and the term ‘intrinsic potency’ refers to the plasma concentration needed to maintain a specified level of neuromuscular block (e.g. EC50).

Factors contributing to the rapid onset of rapacuronium

PK–PD modelling has shown that the rate constant of transport between plasma and effect compartment, the ke0, for rapacuronium is 0.4–0.45 min−1 [3,4], corresponding to an equilibration half-life of 1.6 min. This value of ke0 is markedly higher for rapacuronium than for any of the currently available neuromuscular blocking agents (Figure 1).

Figure 1.
Figure 1.:
Relationship between EC50 (in µmol, logarithmic scale) and ke0 (in min−1) of 14 neuromuscular blocking agents tested in man.

The relevance of this high value ke0 for the short onset of action of rapacuronium has been demonstrated by computer simulations. In Figure 2 the plasma concentration profiles after a bolus dose of rapacuronium and rocuronium have been depicted. For reasons of comparison, the doses were adjusted to achieve a plasma concentration of 10 mg L−1 at 1 min after a bolus dose administration. The time-point of 1 min was chosen to diminish the influence of the complex plasma concentration profile during the first minute after administration of a bolus dose [5]. Over the first 10 min, the plasma concentration of rocuronium decreases only slightly more rapidly than that of rapacuronium; however, after 10 min, rapacuronium concentration decreases more rapidly.

Figure 2.
Figure 2.:
Plasma concentration profiles of rapacuronium (thick line) and rocuronium (thin line). The doses have been adjusted to achieve a plasma concentration of 10 mg L−1 at 1 min after a bolus administration. The plasma concentration profiles have been calculated from mean pharmacokinetic data of rapacuronium [4] and rocuronium (unpublished data), obtained after an infusion over 2–6 min.

The simulated twitch profiles after a bolus dose of rapacuronium and rocuronium, calculated by PK–PD modelling, are shown in Figure 3. For reasons of comparison, the doses have been adjusted to achieve a 95% block after a bolus administration. The onset of action of rapacuronium is markedly faster than for rocuronium, the peak effect being reached after 3.5 min vs. 6.7 min for rocuronium, and the recovery is markedly faster and occurs earlier than after rocuronium. The influence of ke0 and the pharmacokinetics can be clarified by comparison with a hypothetical NMBA with pharmacokinetic properties similar to that of rapacuronium and with a ke0 similar to that of rocuronium (dashed line in Figure 3). Comparison of rapacuronium (ke0 0.449 min−1) and the hypothetical neuromuscular blocking agent (ke0 0.136 min−1) demonstrates that both the onset and offset are governed by ke0. In other words, the rapid onset and offset of rapacuronium, in comparison to rocuronium, is due to its high ke0.

Figure 3.
Figure 3.:
Twitch profiles after administration of rapacuronium (thick line), rocuronium (thin line) and a hypothetical neuromuscular blocking agent with pharmacokinetic properties similar to that of rapacuronium and with a ke0 similar to that of rocuronium (dashed line). The doses have been adjusted to achieve 95% block after a bolus administration. The twitch profiles have been calculated from mean pharmacokinetic-dynamic data of rapacuronium [4] and rocuronium (unpublished data), obtained after an infusion over 2–6 min.

Because the plasma concentration over the first 10 min for both compounds is almost similar, the influence of the pharmacokinetics on the onset time is small; the time to peak of rocuronium of 6.7 min is only marginally longer than that of the hypothetical neuromuscular blocking agent (6.1 min). In contrast, the recovery of the hypothetical neuromuscular blocking agent is markedly faster than for rocuronium, which is due to the more rapid disappearance from plasma after 10 min.

The predominant influence of ke0 on the time to peak effect can be understood from the following equation:

Equation 1 (1)

where C is the plasma concentration, Ce is the effect compartment concentration, and dCe/dt the change of the effect compartment concentration per unit of time. In other words, the net transport rate of neuromuscular blocking agent between plasma and effect compartment is proportional to the concentration gradient between plasma and effect compartment, and to the constant ke0. A high value of ke0 results in a more rapid transport of neuromuscular blocking agent to the effect compartment, and thus to a more rapid increase of the effect compartment concentration. As a consequence, the time to peak effect is shorter.

The question arises as to why the value of ke0 of rapacuronium is much higher than that of other NMBAs? The transport between plasma and effect compartment is likely to be dependent on the following processes:

  • Muscle blood perfusion, which determines the rate of transport to the muscle capillaries [6]. Neuromuscular blocking agents may affect muscle blood perfusion by an effect on cardiac output or by local vasoconstriction or vasodilatation. It has been demonstrated that several neuromuscular blocking agents, including rapacuronium, possess calcium channel blocking properties, and may cause an increase of muscle blood perfusion [7,8]. As a consequence, the transport of neuromuscular blocking agent to the effect compartment may be enhanced, and may result in a higher value for ke0.
  • Diffusion from plasma to interstitial space, and from interstitial space to the neuromuscular junction (synaptic cleft). It seems unlikely that the diffusion coefficient of rapacuronium, rocuronium and vecuronium are markedly different, given the small differences in molecular weight of the cation. Based on their higher molecular weight, the diffusion coefficients of atracurium and mivacurium are likely to be about 25% less than those of the aminosteroidal neuromuscular blocking agents.
  • Rate of binding to/from the acetylcholine receptor (AChR). This process is extremely fast when compared to the pharmacokinetic processes, and does not play a role in the time-course of action.
  • Buffering hypothesis: the concentration of AChR in the synaptic cleft is extremely high. Armstrong and Lester [9] calculated a concentration of 300 µmol, which is about 50 (rapacuronium) to 10 000 (doxacurium) times the concentration of a neuromuscular blocking agent in plasma at 50% neuromuscular block (EC50). As a consequence, the concentration of NMBA bound to AChR in the synaptic cleft will be much higher than the concentration of free NMBA in the synaptic cleft. The net transport of neuromuscular blocking agent between synaptic cleft and plasma is governed by the unbound concentrations in plasma and synaptic cleft, and Equation 1 can be modified to [2,10]:

Equation 2 (2)

where C u and C ue are the unbound concentrations of the neuromuscular blocking agent in plasma and effect compartments, respectively.

The unbound concentration in plasma and effect compartment at 50% neuromuscular block is dependent on the intrinsic potency of the neuromuscular blocking agent, and thus may vary widely between neuromuscular blocking agents (Figure 1). However, the concentration of bound neuromuscular blocking agent, and thus of AChRs occupied by the neuromuscular blocking agent, is independent of the intrinsic potency of the neuromuscular blocking agent; about 85% of AChR is bound to the neuromuscular blocking agent at 50% neuromuscular block [11]. The change of the total amount of neuromuscular blocking agent in the synaptic cleft is governed by Equation 2. For low-potency neuromuscular blocking agents, e.g. rapacuronium, the contribution of the bound neuromuscular blocking agent is relatively small, and the influence of AChRs on the time-course of action is likely to be small. Also on the other hand, for more potent neuromuscular blocking agents, e.g. vecuronium and mivacurium, the contribution of bound neuromuscular blocking agent is much larger. It takes more time to transport the neuromuscular blocking agent to the effect compartment, and as a consequence, the peak effect is reached at a later time-point, and the recovery is delayed [2,10]. This effect of the high concentration of AChR has been called the ‘buffering hypothesis’ [9]. Donati and Meistelman implemented this phenomenon in a PK–PD model [10]. Although the buffering hypothesis has a sound anatomical and physiological basis, convincing evidence that it plays a significant role in the time-course of action of neuromuscular blocking agents is still lacking.

Some indirect evidence may be obtained from a comparison of values for ke0 and EC50 for different neuromuscular blocking agents, obtained by the Sheiner PK–PD model [1], i.e. not taking into account the AChR concentration. Figure 1 shows a clear correlation (r = 0.82) between ke0 and EC50 of 14 NMBAs tested in human beings. This correlation may be explained by the buffering hypothesis. If buffering is not taken into account, the apparent value for ke0 obtained by the Sheiner model (i.e. using Equation 1) will be smaller than the true value, which would be obtained from Equation 2. The more potent the neuromuscular blocking agent, i.e. the lower the value of EC50, the more the calculated ke0 will deviate from its true value, which might be virtually identical for each neuromuscular blocking agent. On the other hand, there is some evidence contradicting the buffering hypothesis. First, the PK–PD modelling of mivacurium was not improved by incorporation of the model of Donati and Meistelman, although mivacurium is among the most potent neuromuscular blocking agents (expressed as EC50 in molar units, see Figure 1) investigated by PK–PD modelling in man [12]. Secondly, we did not find a relation between dose and time to peak effect, as would be predicted by the buffering hypothesis (unpublished data).

Molecular basis of PK–PD characteristics

In principle, the PK–PD properties of any drug must have their origin in the molecular structure. We attempted to gain insight in the relation between molecular structure of a series of aminosteroidal neuromuscular blocking agents, their physicochemical properties, such as lipophilicity, and their PK–PD characteristics, such as plasma protein binding, clearance, ke0 and EC50 [8,13]. Several PK–PD parameters were correlated with lipophilicity, as expressed in the partition coefficient between octanol and water. Plasma protein binding, clearance, ke0 and EC50 increase with increasing lipophilicity. As a net result, onset time decreases duration of action decreases and ED90 increases with increasing lipophilicity. These studies clarified the position of rapacuronium (Org 9487) between the less lipophilic, slower- and longer-acting, and more potent compounds vecuronium and rocuronium and the more lipophilic, faster- and shorter-acting, and less potent compounds Org 9453, Org 9616, and Org 7617. The latter compounds, although promising in animal experiments, failed in humans due mainly to their extremely low potency.

Relation between onset and potency

Bowman and colleagues showed a clear inverse correlation between the effective potency, as expressed by ED50 and the onset time, i.e. the time to maximum twitch depression, for a series of 20 aminosteroidal neuromuscular blocking agents in the cat [14]. This relation has also been established in human beings [13,15,16]. It implies that a neuromuscular blocking agent with a short onset of action will inevitably possess the disadvantage of a low potency, requiring relatively high dosing which may increase the risk of side-effects. There are at least two possible explanations for this inverse relationship [2]: (a) differences in clearance may affect both effective potency and onset time, and thus may explain the observed relationship [17], and (b) the buffering hypothesis, as discussed above. It remains unclear which factor contributes most to the observed inverse correlation between effective potency and onset time.

Relation between PK–PD characteristics and intubation conditions

The time-course of action of neuromuscular blocking agents is usually measured at the adductor pollicis after stimulation of the ulnar nerve. It is recognized, however, that the time-course at the adductor pollicis may be different from the muscles relevant to intubation. Therefore the time-course at the adductor pollicis is not necessarily a good indicator of intubation conditions.

Donati and colleagues developed a method for monitoring the relaxation of the laryngeal muscles by measuring the pressure changes in the cuff of the tracheal tube positioned between the vocal cords [18]. The time-course and PK–PD parameters at the laryngeal muscles were different from those at adductor pollicis for vecuronium, rocuronium and rapacuronium. The time to peak was shorter as a result of a higher ke0 [3,19,20], being 0.630 min−1 for the laryngeal adductors and 0.405 min−1 for the adductor pollicis for rapacuronium [3]. The laryngeal muscles were less sensitive to vecuronium and rocuronium, resulting in a higher EC50. In contrast, the sensitivity of both muscles to rapacuronium was similar, which may contribute to the good intubation conditions after a relatively moderate dose of rapacuronium.

Factors contributing to the rapid offset of rapacuronium

Many of the factors responsible for the rapid onset of a neuromuscular blocking agent may also contribute to a rapid offset. A rapid disappearance from plasma and a high ke0 value increase the rate of both onset and offset of neuromuscular block. However, the relative contribution of these factors is different during onset and offset. As shown in Figure 3, a decrease of ke0 markedly affects the recovery index and duration to 90% recovery. In addition, a lower clearance increases the speed of offset significantly.

The relatively short duration of rapacuronium may be prolonged after repeated administration or continuous infusion over a period of 1h or longer [21,22]. The slower recovery is due to two factors:

  • (a) Accumulation of the drug in deeper compartments, resulting in an increased context-sensitive half-life. This is a common phenomenon for drugs whose duration of action terminates as a result of distribution rather than elimination, e.g. vecuronium and rocuronium.
  • (b) Formation of the metabolite, 3-desacetyl-rapacuronium (Org 9488), which has a markedly lower clearance and a longer half-life than the parent compound [4]. In addition, the intrinsic potency of this metabolite is about 2.5 times higher than that of rapacuronium.

Early reversibility

Wierda and colleagues [23] demonstrated that the duration of neuromuscular block after an intubation dose of rapacuronium could be reduced significantly by the administration of neostigmine 2 min after the administration of rapacuronium, i.e. during complete block. In contrast, the duration of an intubation dose of rocuronium could not be shortened by administration of neostigmine after 2 min when compared to reversal at 25% recovery of the twitch height [24]. The difference between rapacuronium and rocuronium was explained using PK–PD modelling [23,24]. The combination of the increased amount of acetylcholine at the neuromuscular junction by administration of the anticholinesterase drug and the high plasma clearance of rapacuronium result in a fast recovery from neuromuscular block. The rate of recovery is now determined by the transport of neostigmine from plasma to the neuromuscular junction and by the rate of disappearance of rapacuronium from plasma.

Comparison with other neuromuscular blocking agents

The simulations in Figures 2 and 3 demonstrate that differences in onset times between neuromuscular blocking agents may be explained largely by differences in ke0. The high value of ke0 was shown to be responsible for the rapid onset and offset of rapacuronium when compared to rocuronium and vecuronium. In addition, plasma clearance may play a dominant role in the onset time, as was shown by Beaufort and his colleagues [17]. Mivacurium has a rapid plasma clearance, which approaches that of succinylcholine. Nevertheless, the onset time is relatively long due to the small value of ke0. Mivacurium is among the most potent NMBAs (Figure 1). Therefore its small ke0 may be related to the high intrinsic potency according to the buffering hypothesis. However, a PK–PD analysis taking into account the buffering hypothesis could not explain the low value of ke0 [12].

Due to the lack of a sensitive bioanalysis, the PK–PD properties of succinylcholine are still largely unknown. Taking into account the small molecular size and the rapid onset of action, it is likely that ke0 is large. It remains unclear whether or not the depolarizing mechanism of action of succinylcholine plays a role in its short onset of action.

Conclusions

The rapid onset and offset of rapacuronium can be explained from its pharmacokinetic and pharmacodynamic characteristics. A unique property of rapacuronium is its high value ke0, indicating a rapid access to the receptor site. The reason for this high ke0 remains speculative. Further research on biophase kinetics may reveal the mechanisms involved, and may also lead to new drugs and new concepts in the search for the relaxant providing ideal intubating conditions at an early time.

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Keywords:

NEUROMUSCULAR BLOCKING AGENTS; rapacuronium; PHARMACODYNAMICS; onset; offset; PHARMACOKINETICS; clearance; rate constants

© 2001 European Society of Anaesthesiology